A sense of respiratory discomfort or difficulty in breathing ("dyspnea") is a cardinal symptom of many respiratory and cardiovascular diseases. Respiratory discomfort can stem from a number of afferent sources which can produce a variety of perceived sensations. This proposal seeks to examine the basic mechanisms underlying one prominent respiratory sensation, "air hunger", the uncomfortable urge to breathe perceived during breath hold or during insufficient pulmonary ventilation. The specific aims are: 1) characterize the stimulus-response relationships and determine relative importance of peripheral and central chemoreceptors in air hunger perception; (2) determine the mechanism whereby breathing diminishes air hunger; 3) determine whether a copy of respiratory motor commands from the medulla, sent to the forebrain, generates air hunger; and 4) examine aspects of respiratory control in highly unusual patients and during unusual interventions encountered in experiments conducted primarily to address specific aims 2 and 3. For example, experiment F affords the opportunity to observe the ventilatory response to exercise in the absence of automatic drive to breathe; experiment C affords the opportunity to observe the stability and efficacy of control when the respiratory muscles are replaced by a mechanical servo-ventilator in quadriplegic patients. In the proposed work, air hunger will be elicited by increasing inspired CO2 and subjects will rate the intensity of perceived air hunger using psychophysical techniques developed in earlier work. Various interventions will be employed to determine their effect on CO2-induced air hunger and thereby deduce underlying mechanisms; these include conventional mechanical ventilation, servo-driven mechanical ventilation controlled by the subject, hypoxia, and exercise. Ventilator-dependent quadriplegics, and patients with congenital lack of automatic respiratory centers in the brainstem will be studied in order to define neural pathways. What is learned about patient control of servo-ventilators may be of practical value to chronically ventilator-supported patients. The larger goal of these studies is to improve the understanding of basic mechanisms underlying respiratory sensation, which is likely to lead to better diagnosis and symptom relief.